Each year an estimated 400,000 people globally, among them 30,000 Americans, are newly diagnosed with oral squamous cell carcinoma (OSCC). The 5-year survival rate is only about 50%, accounting for 1 death every hour in the US. Following the surgical removal of tumor, selection of adjuvant treatment is made largely based on the clinical stage of the tumor. However, despite the advances in treatment, survival rate has not improved significantly over the last several decades. Discovery of a strategy to identify cancer patients with poor prognosis and selectively directing those patients for additional adjuvant chemo/radiation therapy will significantly improve the cancer survival rate. Hence, it is imperative to discover a reliable and accurate prognostic indicator of oral cancer survival to be applied in the treatment decision making process and improve the overall survival of patients with oral cancer. The aim of the proposed study is to develop and validate a microRNA (miR) marker-based prognostic modality for oral cancer survival (5-year disease free survival versus death within 5-years). Those with less favorable prognosis with surgery alone may then be directed for additional treatment. In the initial phase of the study, we propose to perform a genome-wide miR expression assessment via next generation sequencing in 10 OSCC tissue samples from patients who had 5-year disease-free survival (Group 1), compared with 10 of those from age- and gender-matched cancer patients who died of the disease within 5 years (Group 2). Bioinformatics analysis will be performed to integrate sequencing data to identify miR target genes and miR-mediated oncogenic network and pathways. Top miR candidates that can identify those patients with poor prognosis with high sensitivity and specificity will be selected to form a prognostic miR marker panel in Aim 1. The candidate marker panel will then be validated in Aim 2 in additional 40 Group 1-Group 2 pairs using RT-qPCR. The proposed innovative approach has never been applied for prognosis of oral cancer survival before; it offers scalability and cost containment while allowing an agnostic approach to discovery of molecular changes across the genome that is followed by independent validation. Developing a new generation of dental scientists able to translate basic science into actionable clinical information and methods is imperative to progress. This NIDCR Small Grant Program for New Investigators (R03) proposal describes a 2-year research program aimed at developing highly specialized expertise in the molecular management of OSCC. The proposed study will serve as the candidate's platform to develop and fine-tune practical experience and skills in patient-oriented research, to establish independence in the area of oral cancer research, obtain preliminary data that may be used in the near future to support R01 applications and to expand the field of oral carcinogenesis towards a better understanding of this deadly disease. Through this R03 program for the new investigators, the candidate will reach her long-term goal of becoming an independent investigator with expertise in the management of oral cancer.